Neovascularization occurs when either there is proliferation of blood vessels in tissues that would otherwise not contain or there is a growth of a different kind of blood vessel in a tissue. Unwanted neovascularization is associated with a number of disease conditions, such as that seen to occur with tumor growth or vision loss. One example of undesirable neovascularization in the eye is choroidal neovasculature (CNV) like that found in the “wet” form of age-related macular degeneration (AMD).
AMD causes severe, irreversible vision loss and is the leading cause of blindness in individuals older than 50 years in the Western World. Most patients have the non-neovascular (“dry”) form, characterized by drusen and abnormalities of the retinal pigment epithelium (RPE). Eighty to ninety percent of the severe vision loss due to AMD, however, is attributable to the form characterized by CNV, also called “wet” AMD. In the United States, between 70,000 to 200,000 individuals over the age of 65 develop the neovascular form of AMD every year (Bressler, N. “Submacular surgery: Are randomized trials necessary?” Arch Ophthalmol. 1995; 113; 1557-1560; Klein, R. et al. “The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study.” Ophthalmol. 1997; 104(1):7-21).
In CNV, the newly formed vessels have a tendency to leak blood and fluid, causing symptoms of scotoma and metamorphopsia (Macular Photocoagulation Study Group. “Argon laser photocoagulation for neovascular maculopathy. Three-year results from randomized clinical trials.” Arch Ophthalmol. 1986; 104:694-701). The new vessels are accompanied by proliferation of fibrous tissue (Macular Photocoagulation Study Group. “Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials.” Arch Ophthalmol. 1993; 111:1200-1209). This complex of new vessels and fibrous tissue can destroy photoreceptors within 3 to 24 months. At the same time that existing CNV is destroying retinal tissue where it has formed, the lesion can continue to grow throughout the macula, resulting in progressive, severe and irreversible vision loss. Without treatment, most affected eyes will have poor central vision (<20/200) within 2 years (Macular Photocoagulation Study Group. “Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy.” Arch Ophthalmol. 1986; 104:503-512). In addition, when one eye of an individual develops CNV, the fellow eye has about a 50% chance of developing a similar CNV lesion within 5 years (Treatment of Age-related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. “Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with VISUDYNE: One-year results of 2 randomized clinical trials—TAP report 1.” Arch Ophthalmol. 1999; 117:1329-1345).
Photodynamic therapy (PDT) offers an approach to selectively destroy CNV without significant destruction of overlying retina tissue, possibly by occluding the new vessels within the CNV lesion. Photodynamic therapy is a two-step process consisting of an intravenous injection of a photosensitizer (light-activated drug) followed by light application (Marcus, S. “Photodynamic therapy of human cancer: clinical status, potential and needs.” In: Gomer C, ed. Future Directions and Application In Photodynamic Therapy. Berlingham: SPIE Press. 1990; IS6:5-56; Manyak, M. J. et al. “Photodynamic therapy.” J Clin Oncol. 1988; 6:380-391; Roberts, W. G. et al. “Role of neovasculature and vascular permeability on the tumor retention of photodynamic agents.” Cancer Res. 1992; 52(4):924-930). The light sources most commonly used are non-thermal lasers or light emitting diodes (LEDs). Photosensitizers may preferentially accumulate in neovascular tissues, including the endothelial cells of choroidal neovascularization. In combination with localized light administration, this allows for selective treatment of the pathologic tissue (Kreimer-Birmbaum, M. “Modified porphyrins, chlorins, phthalocyanines, and purpurins: second generation photosensitizers for photodynamic therapy.” Semin Hematol. 1989; 26:157-173; Moan, J. et al. “Photosensitizing efficiencies, tumor and cellular uptake of different Photosensitizing drugs relevant for photodynamic therapy of cancer.” Photochem Photobiol. 1987; 46:713-721). After exposure to light at a wavelength of 689 nm, an energy transfer cascade is initiated, culminating in the formation of singlet oxygen which generates intracellular free radicals (Kreimer-Birmbaum, M., supra; Roberts, W. G. et al. “In vitro photosensitization I. Cellular uptake and subcellular localization of mono-1-aspartyl chlorin e6, chloro-aluminum sulfonated phthalocyanine, and Photofrin II.” Lasers Surg. Med. 1989; 9:90-101). These free radicals can disrupt cellular structures such as the cell membrane, mitochondria, and lysosomal membranes.
Visudyne® photodynamic therapy gained US marketing approval in 2000 and was approved for the treatment of patients with predominantly classic subfoveal CNV due to AMD. Visudyne therapy targets the vascular component of CNV. Its approved two-step process is one by which verteporfin, a light-activated drug (photosensitizer) delivered by intravenous (IV) infusion, is administered and then followed by nonthermal laser light application (50 J/cm2 delivered at 600 mW/cm2 over 83 seconds) to the CNV lesion.
Treatment of CNV using other therapies, including the use of PDT in combination with additional therapies is known in the art. Macugen® (pegaptanib) is an anti-VEGF therapy indicated in all patients with CNV due to AMD. Lucentis® (ranibizumab) is another anti-VEGF therapy indicated in all patients with CNV due to AMD (Rosenfeld P J, Brown D M, Heier J S, et al, for the MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J. Med. 2006; 355:1419-1431; Brown D M, Kaiser P K, Michels M, et al, for the ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1432-1444; Lucentis® (ranibizumab injection) prescribing information. San Francisco, Calif.: Genentech; 2006. http://www.gene.com/gene/products/information/tgelucentis/index.jsp. Accessed Nov. 15, 2006). The Lucentis regimen as defined in the US package insert (Lucentis® (ranibizumab injection) prescribing information. San Francisco, Calif.: Genentech; 2006. http://www.gene.com/gene/products/information/tgelucentis/index.jsp. Accessed Nov. 15, 2006) states “Lucentis 0.5 mg (0.05 mL) is recommended to be administered by intravitreal injection once a month. Although less effective, treatment may be reduced to one injection every three months after the first four injections if monthly injections are not feasible. Compared to continued monthly dosing, dosing every 3 months will lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following 9 months. Patients should be evaluated regularly.”
Avastin® (bevacizumab) is an anti-VEGF monoclonal antibody that has been reported in the literature as having been used as an intravitreal injection to treat patients with CNV due to AMD, but it is not currently approved for this use. Case series of Avastin treatment for patients with AMD and other retinal diseases have been published and show an increase of mean VA in treated patients (Avery R L, Pieramici D J, Rabena M D, Castellarin A A, Nasir M A, Giust M J. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration, Ophthalmology, 2006; 113(3):363-372; Bashshur Z F, Bazarbachi A, Schakal A, Haddad Z A, El Haibi C P, Noureddin B N. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J. Ophthalmol. 2006; 142:1-9; Costa R A, Jorge R, Calucci D, Cardillo J A, Melo L A S, Scot I U. Intravitreal bevacizumab for choroidal neovascularization caused by AMD (IBeNA Study): Results of a phase I dose-escalation study. Invest Ophthalmol Vis Sci. 2006; 47:4569-4578; Spaide R F, Laud K, Fine H F, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration, Retina, 2006; 26:383-390; Rich R M, Rosenfeld P J, Puliafito C A et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration, Retina, 2006; 26:495-511).
Combination therapies using Visudyne with the intravitreal anti-VEGF therapies include Macugen (Eyetech Study Group. Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase II study results. Ophthalmology 2003; 110(5):979-986), Lucentis (Heier J S, Boyer D S, Ciulla T A, et al. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: Year 1 results of the FOCUS study. Arch Ophthalmol. 2006; 124:1532-1542; Schmidt-Erfurth U, Gabel P, Hohman T, Protect Study Group. Preliminary results from an open-label, multicenter, phase II study assessing the effects of same-day administration of ranibizumab (Lucentis™) and verteporfin PDT (PROTECT Study). Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); May 2, 2006; Fort Lauderdale, Fla., USA; Schmidt-Erfurth U, Gabel P, Hohman T, Protect Study Group. Preliminary results from an open-label, multicenter, phase II study assessing the effects of same-day administration of ranibizumab (Lucentis™) and verteporfin PDT (PROTECT Study). Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); May 2, 2006; Fort Lauderdale, Fla., USA; Funk M, Michels S, Wagner J, Kiss C, Sacu S, Schmidt-Erfurth U. Vascular effects of combined ranibizumab (Lucentis®) and verteporfin (Visudyne®) therapy in patients with neovascular age-related macular degeneration. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); Apr. 30, 2006; Fort Lauderdale, Fla., USA; Wagner J, Simader C, Kiss C, Michels S, Sacu S, Schmidt-Erfurth U. Changes in functional macular mapping in patients with neovascular age-related macular degeneration receiving combination of verteporfin (Visudyne®) and ranibizumab (Lucentis™) therapy. Poster presented at Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); Apr. 30, 2006; Fort Lauderdale, Fla., USA; Wolf S, Gabel P, Hohman T C, Schmidt-Erfurth U. Fluorescein angiographic and OCT results from an open-label, multicenter, phase II study assessing the effects of same-day ranibizumab (Lucentis™) and verteporfin PDT (Visudyne®). Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); May 3, 2006; Fort Lauderdale, Fla., USA), and Avastin (Dhalla M S, Shah G K, Blinder K J, Ryan E H Jr, Mittra R A, Tewari A. Combined photodynamic therapy with verteporfin and intravitreal bevacizumab for choroidal neovascularization in age-related macular degeneration, Retina, 2006; 26(9):988-993; Eter N, Ladewig M, Hamelmann V, Helb H M, Karl S, Holz F G. Combined intravitreal bevacizumab (Avastin) and photodynamic therapy for AMD. Poster presented at Annual Meeting of the American Academy of Ophthalmology (AAO), Nov. 12, 2006, Las Vegas, Nev. Abstract available at: http://www.aao.org/annual_meeting/program/onlineprogram06.cfm. Accessed on Nov. 24, 2006), have been evaluated in clinical trials and case series in subjects with AMD.
Combination therapy using Visudyne with intravitreal triamcinolone acetonide has previously been reported (Augustin A J, Schmidt-Erfurth U. Verteporfin therapy combined with intravitreal triamcinolone in all types of choroidal neovascularization due to age-related macular degeneration, Ophthalmology, 2006; 113(1):14-22; Spaide R F, Sorenson J, Maranan L. Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization, Ophthalmology, 2003; 110(8):1517-1525; Rechtman E, Danis R P, Pratt L M, Harris A. Intravitreal triamcinolone with photodynamic therapy for subfoveal choroidal neovascularisation in age related macular degeneration, Br J. Ophthalmol. 2004; 88(3):344-347; Van De Moere A, Sandhu S S, Kak R, Mitchell K W, Talks S J. Effect of posterior juxtascleral triamcinolone acetonide on choroidal neovascular growth after photodynamic therapy with verteporfin, Ophthalmology, 2005; 112(11):1897-1903; Nicolo M, Ghiglione D, Lai S, Nasciuti F, Cicinelli S, Calabria G. Occult with no classic choroidal neovascularization secondary to age-related macular degeneration treated by intravitreal triamcinolone and photodynamic therapy with verteporfin, Retina 2006; 26(1):58-64; Augustin A J, Schmidt-Erfuth U. Verteporfin and intravitreal triamcinolone acetonide combination therapy for occult choroidal neovascularization in age-related macular degeneration, Am J. Ophthalmol. 2006; 141:638-645; Ruiz-Moreno J M, Montero J A, Barile S, Zarbin M A. Photodynamic therapy and high-dose intravitreal triamcinolone to treat exudative age-related macular degeneration: 1-year outcome, Retina, 2006; 26:602-612). Triple therapy with Visudyne, an anti-VEGF therapy, and a steroid has also been reported (Colina-Luquez J M, Liggett P E, Tom D, Chaudhry N A, Haffner G, Cortes C F. Prospective and preliminary study evaluating triple therapy of intravitreal triamcinolone, photodynamic therapy and pegaptanib sodium for choroidal neovascularization. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); Apr. 30, 2006; Fort Lauderdale, Fla., USA; Offermann I, Altinay A, Schmidt-Erfurth U, Augustin A J. Intravitreal bevacizumab for the treatment of remaining choroidal neovascularization (CNV) activity following combination therapy (PDT and triamcinolone). Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); May 1, 2006; Fort Lauderdale, Fla., USA; Augustin A J, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina. 2007; 27:133-140).
What is needed are additional methods of photodynamic therapy that can reduce the number of retreatments required following first treatment and that have acceptable visual acuity outcomes and acceptable safety profiles.